ACTIVATION OF CYTOKINE PRODUCTION, TUMORICIDAL PROPERTIES, AND TYROSINE PHOSPHORYLATION OF MAPKS IN HUMAN MONOCYTES BY A NEW SYNTHETIC LIPOPEPTIDE, JBT3002

We investigated the expression of cytokine genes and tumoricidal prope rties in human blood monocytes in response to a new synthetic immunomo dulating Lipopeptide, JBT3002. Incubation of peripheral blood monocyte s with free-form JBT3002 or JBT3002 encapsulated in multilamellar phos pholipid vesicles (liposomes, MLV-JBT3002) induced tumoricidal propert ies in a dose-dependent manner. Both MLV-JBT3002 and free-form JBT3002 induced production of tumor necrosis factor alpha, interleukin-1 beta , and interleukin-6 in a dose-dependent manner with similar kinetics, Treatment of monocytes with interferon-gamma did not significantly alt er the expression of cytokine genes but increased the expression of cy tokines induced by MLV-JBT3002 and free-form JBT3002, In contrast to m onocyte activation hy lipopolysaccharide (LPS), activation by JBT3002 was independent of serum and was not inhibited by CD14-neutralizing an tibody. Incubation of monocytes with JBT3002 induced a rapid increase in tyrosine phosphorylation of proteins with apparent molecular masses of 42 and 38 kDa, a migration band shift of c-Jun NH2-terminal kinase 1 (JNK1), and activation of extracellular signaling regulated kinases . Consistent with its effect on cytokine expression, stimulation of th ese intracellular signaling pathways by JBT3002 was not inhibited in s erum-free conditions. Collectively the data indicate that the syntheti c Lipopeptide JBT3002 is a potent monocyte activator that modulates mo nocyte function by mechanisms similar to LPS but by a distinct recepto r.